Since its discovery in 1957, interferon has been extensively studied. Although initially considered as an antiviral substance, evidence has accumulated that interferon also has anti-tumor activity. These are many reports in the literature of clinical studies with interferon in cancer. These are summarized, for example, in Priestman, P. J. "Interferon: an Anti-Cancer Agent?" Cancer Treatment Reviews (1979) 6, 223-237. See also Sikora, K. "Does Interferon Cure Cancer?" British Medical Journal, Sept. 27, 1980, 281 (6244) 855-8. All of these clinical tests have required enormous amounts of interferon, usually in the range of from 3,000,000 to 10,000,000 units of interferon per day, administered until remission, complication, or lack of adequate therapeutic response dictates a halt in therapy. Notwithstanding such enormous amounts of interferon, the results of these clinical trials have not yet proven particularly effective, other than to cause a slight increase in the average survival time of the cancer patients. The extremely high dose rates used for cancer treatment should be contrasted to the low dose therapy using only thousands of units which has been reported as efficaceous in aborting and treating common "cold" and flu symptoms with interferon.
These high dose rates have known side effects which include myelosuppression, pyrexia, etc. In view of the large dosages required, the known side effects, and the high price of interferon, it appears that, in the manner in which it is used to date, interferon is a failure for the treatment of cancer.
It is the belief of the present inventor that the reason why interferon fails, even while administered in very large amounts, is because of denaturation of the interferon in vivo due to a substance known to be produced in persons with malignant diseases.
It is known from Chen. Y. M. et al "Serum Tyrosinase in Malignant Disease, Its Activity, and the Electrophoretic Patterns of the Enzyme as Carried by Immunoglobulins", Cancer Research, 39, 3485-90, September, 1979, that most malignant tumors exhibit an abnormally high tyrosinase activity so that the level of tyrosinase that is transferred to the serum is between 50% and 600% higher than the tyrosinase activity of normal individuals.
It is also known that tyrosinase not only attacks the amino acid tyrosine but also attacks tyrosine when contained in the polypeptide chain of a protein. In fact, it has been shown in the review Sizer, I. W. "Oxidation of Proteins by Tyrosinase and Peroxidase," Advances in Enzymology, 14, 129-159 (1953), that many proteins are biologically inactivated by tyrosinase in view of the oxidation of the tyrosyl groups in the protein by the tyrosinase.
Interferon is a protein of low molecular weight whose amino acid composition includes substantial amounts of tyrosine. It has been reported that chick embryo interferon contains 2.3% tyrosine. It has also recently been reported that human fibroblast interferon contains 4.4% tyrosine, and that tyrosine is the third amino acid in the amino-terminal amino acid sequence of the human fibroblast interferon. Furthermore, it has recently been reported that human lymphoblastoid interferon contains 2.3% tyrosine.
That denaturation of interferon is indeed actually caused by tyrosinase has been proved by the present inventor in the following experiment.
Tyrosinase in the amount of 0.01 mM was incubated in vitro with 5000 units of human leucocyte interferon for 30 minutes. In the course of this incubation the color of the interferon turned from substantially transparent to brown. Such a color change is one indication of denaturation. Measurement of oxidation demand during this incubation also demonstrated that oxidation took place.
Accordingly, the present inventor believes that interferon fails to exert its activity on most malignancies because of the denaturating enzymatic process to which it is subjected first in the blood and then at the cancer site, by the tyrosinase of the malignant growth.